Genome-Guided Therapeutic Vulnerabilities in Esophageal Cancer

项目3摘要 食管癌是一种常见且致命的疾病，治疗方法不足。系统治疗仍然 依赖于经验性化疗，在姑息治疗中单独给药，并与放射联合给药， 辅助护理。我们对癌症基因组的快速扩展的知识与 无数靶向药物的开发创造了一个新的独特的机会来推进理性， 生物标志物驱动的食管癌治疗。我们对食管癌的基因组研究 鉴定了两类主要的靶：靶向受体酪氨酸激酶的高度重复扩增， 最常见的是EGFR和ERBB 2（Her 2），以及细胞周期、细胞周期蛋白D1、细胞周期蛋白E1和细胞周期蛋白E2的扩增调节剂。 CDK6。尽管这些目标和可用的和新兴的抑制剂的强大的基因组理论，我们缺乏 临床前数据，以指导开发策略，利用这些目标。因此，我们建议 开发针对具有受体酪氨酸靶向基因组改变的食管癌的策略 利用基因组学表征的模型系统在体外和体内研究激酶和细胞周期介质 测试治疗剂。我们将测试关于靶向肿瘤的方法的假设， 靶向治疗和合理组合。在整个提案中，我们将努力与其他 本项目资助的项目，并通过本项目广泛使用核心资源，并评估 食管鳞癌和食管腺癌的靶向治疗策略。在 目的1，我们建议评估细胞周期激酶CDK 2作为食管癌的治疗靶点， 在食管癌模型中使用基因组和药理学工具评估该靶点， 病变使它们更可能依赖于CDK 2，编码细胞周期蛋白D1的基因扩增， 细胞周期蛋白E1。在目标2中，我们评估了不同类别的小分子和抗体酪氨酸激酶抑制剂， 具有导致ERBB家族致癌激活的基因组改变的食管癌模型系统 激酶EGFR和ERBB 2。此外，在目标2中，我们还测试了增强ERBB导向的效应的能力。 通过与MAPK或PI 3-K通路的抑制剂组合在食管癌模型中的治疗。 最后，在目标3中，我们评估了我们观察到的食管癌经常携带的现象， 在同一肿瘤中影响细胞周期介质和ERBB家族激酶的基因组畸变， 这表明组合这两组靶点的抑制剂可能对这些肿瘤有效。我们 因此，建议表征这些靶点在这些基因组中共同出现的模式， 癌症和它们在大组组织样品中的共表达。此外，我们还将使用以下示例： EGFR和Cyclin D1共扩增的食管癌模型，以系统地评估 将抑制剂与这些途径结合的不同方法。这三个目标旨在共同追求 具体的假设，使我们能够更快地开发新的更有效的治疗策略， 这些致命疾病的患者。

PROJECT 3 ABSTRACT Esophageal cancer is a common and deadly disease with inadequate therapies. Systemic therapy remains reliant upon empiric chemotherapy, given alone in the palliative setting and in conjunction with radiation for adjuvant care. The convergence of our rapidly expanding knowledge of the cancer genome and the development of a myriad of targeted agents has created a new and unique opportunity to advance rational, biomarker-driven therapies for esophageal cancer. Our genomic studies of esophageal cancers have identified two dominant classes of targets: highly recurrent amplifications targeting receptor tyrosine kinases, most frequently EGFR and ERBB2 (Her2), and amplified modulators of the cell cycle, Cyclin D1, Cyclin E1 and CDK6. Despite strong genomic rationale for these targets and the available and emerging inhibitors, we lack pre-clinical data to guide the development strategies to exploit these targets. Therefore, we propose to develop strategies to target esophageal cancers harboring targetable genomic alterations of receptor tyrosine kinases and of cell cycle mediators utilizing genomically-characterized model systems in in vitro and in vivo testing of therapeutic agents. We will tests hypotheses regarding means to target tumors, both with single targeted therapies and with rational combinations. Throughout this proposal, we integrate efforts with the other projects in this Project Grant and make extensive use of core resources through this Project and evaluate targeted strategies that for both esophageal squamous cell carcinoma and esophageal adenocarcinoma. In Aim 1, we propose to evaluate the cell cycle kinase CDK2 as a therapeutic target in esophageal carcinomas by evaluating this target using genetic and pharmacologic tools in esophageal cancer models with genomic lesions that make them more likely dependent upon CDK2, amplifications of genes encoding cyclin D1 and cyclin E1. In Aim 2, we evaluate distinct classes of small molecule and antibody tyrosine kinase inhibitors in esophageal cancer model systems with genomic alterations leading to oncogenic activation of ERBB family kinases EGFR and ERBB2. Furthermore, in Aim 2 we also test the ability to augment effects of ERBB-directed therapy in esophageal cancer models by combinations with inhibitors of either the MAPK or PI3-K pathway. Finally, in Aim 3 we evaluate the phenomena we have observed that esophageal cancers often harbor genomic aberrations impacting both cell cycle mediators and ERBB-family kinases in the same tumor, suggesting that combining inhibitors of these two sets of targets may be efficacious for these tumors. We therefore propose to characterize the patterns of co-occurrence of these targets in the genomes of these cancers and their co-expression in a large panel of tissue samples. Additionally, we will utilize the example of esophageal cancer models with co-amplification of both EGFR and Cyclin D1 to systematically evaluate distinct methods of combing inhibitors to these pathways. Together, these three aims are designed to pursue specific hypotheses that will allow us to much more rapidly develop new more effective therapeutic strategies for patients with these deadly diseases.